86 Multiple dysostosis in Hurler’s disease: a report of three cases

Abstract Introduction Hurler syndrome is the most severe form of mucopolysaccharidosis type I (MPS I), It is a hereditary, metabolic disorder due to an enzymatic deficiency in alpha-Liduronidase with tissue accumulation of glycosaminoglycans (GAGs) leading gradually to chronic multiple visceral dysfunction. We report three cases of multiple dysostosis in Hurler's disease. Case 1: Mr S.O, 26 years old man, presenting a dysmorphic syndrome associating short stature, facial dysmorphism, dental staining, gingival retractions, recurrent bronchial infections, mitral valve disease and joint deformities with a tunnel syndrome. Alpha L iduronidase dosage was performed confirming the diagnosis of Hurler's disease. The radiological assessment showed thickening of the cranial vault with poorly developed paranasal sinuses. Vertebral bodies collapse with oval shape, thoracolumbar kyphosis, hypoplasia of the iliac bones and the superior acetabular region, coxa-valga, with dysplastic femoral heads; cortical thinning of the long bones with a tapered appearance of the distal portions of the radius and ulna, small and deformed carpal bones, thin metacarpal bones, and dysplastic interphalangeal joints. Case 2: Patient B.M 17 years old girl, born of a consanguineous marriage, presenting with a malformation syndrome with short stature, facial dysmorphism, umbilical hernia, valvular heart disease, hepatomegaly, joint stiffness and deformity. Standard x-rays revealed macrocephaly with thickening of the cranial vault, flattened mandibular condyles, with hypertrophy of the clinoid processes; pectus excavatum, platyspondyly with thoracolumbar kyphoscoliosis, small and narrowed pelvis, enlarged and obliquus cotyles, coxa-valga with dysplastic femoral heads; long curved bones with metaphyseal and diaphyseal enlargement, short and enlarged proximal and intermediate phalanx and hypoplastic distal phalanx. Case 3: Patient D.W, 31-year-old female, born of a consanguineous marriage. The patient’s physical examination shows a dysmorphic syndrome with short stature, facial dysmorphism, corneal opacity, recurrent otorhinolaryngological and bronchial infections, joint deformities with carpal tunnel syndrome. An alpha L iduronidase assay was performed confirming the diagnosis. The radiological assessment revealed macrocephaly, thickening of the cranial vault, an elongated J-shaped sella turcica, a short thorax, short and thick clavicles, widened, oar-shaped ribs tapering at their vertebral insertion, “spur” vertebrae, thoracolumbar kyphoscoliosis, narrowed pelvis with coxa-valga and genu valgum, small and deformed carpal and tarsal bones with cortical thinning of long bones. Discussion The term dysostosis multiplex is used to describe skeletal abnormalities seen in MPS I that are often early and prominent. The progressive accumulation of GAGs led to an increase in chondrocyte apoptosis favoring the production of pro-inflammatory cytokines (TNFα, IL-1), chemokines and metalloproteases. This results in a degradation of the cartilaginous matrix, increased by the mechanical stresses, the disturbance of endochondral ossification, particularly in the sites subjected to articular mechanical stresses. That could explain the focal defect of the ossification of certain cartilaginous sites leading to this multiple dysplasia. At the axial level, the vertebrae can be oval shaped and flattened (platyspondyly). In the lower limbs, coxo-femoral abnormalities (coxa valga, splayed or flattened acetabulum), epiphyseal alterations, genu valgum, and hypoplasia of the iliac bones can be found. The metacarpal bones take on a tapered appearance like sucked candy cane and the interphalangeal joints of the hands and feet are dysplastic. Hypoplasia of the odontoid process leads to potentially serious cervical instability. Regular monitoring by MRI is necessary to avoid the risk of spinal cord section. The early introduction of enzyme replacement therapy led to a slower progression of symptoms, with improved growth, joint mobility and physical capacity, and stability over time, especially when associated with an appropriate rehabilitation care. Conclusion Even if Hurler syndrome is rare, it is still underdiagnosed, it can give various and varied clinico-radiographic features and potentially severe disabilities. Early diagnosis is essential since enzyme replacement therapy could stop or slow down the evolution to irreversible tissue damage.


Objectives
To review the epidemiological, and bio-clinical, characteristics of a c-SLE case series.

Methods
The files of patients diagnosed as c-SLE in the pediatrics department of Monastir, Tunisia from January 2004 to March 2022 were reviewed. Mean and standard-deviation were used to express normally-distributed variables, as verified by the Kolmogorov-Smirnov statistical test.

Results
Fourteen patients were collected. Female to male ratio was 6:1. Mean ages at lupus onset and diagnosis were 9.9 AE 1.4 years, [5-13.8 years] and 10.75 AE 2.3 years [6-14 years], respectively. Only two children had a family history of autoimmune disease. The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting. The physical examination noted various abnormalities. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all in keeping with lupus. The musculoskeletal manifestations were arthralgia (71.4%), arthritis and myositis (14.3%). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were proteinuria in 7, haematuria in 6, and hypertension in 2 (with renal failure in one of the patients). The renal biopsy that was performed in one subject showed a class 2 lupus nephritis. Pleural effusion was observed in 3, pneumonia in 3, pericarditis in 2, myopericarditis in 1 and central nervous system (CNS) lupus in 1. Relevant results of the laboratory workup are illustrated in the following The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in two of the subjects respectively. The therapeutic management was based on corticosteroids in 11 cases, hydroxychloroquine in 3, while cyclophosphamides and immunoglobulin were used for two subjects respectively. The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal.

Conclusion
Childhood-onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early-stage diagnosis, therefore preventing the serious complications of the disease.

Introduction
Hurler syndrome is the most severe form of mucopolysaccharidosis type I (MPS I), It is a hereditary, metabolic disorder due to an enzymatic deficiency in alpha-Liduronidase with tissue accumulation of glycosaminoglycans (GAGs) leading gradually to chronic multiple visceral dysfunction. We report three cases of multiple dysostosis in Hurler's disease. The patient's physical examination shows a dysmorphic syndrome with short stature, facial dysmorphism, corneal opacity, recurrent otorhinolaryngological and bronchial infections, joint deformities with carpal tunnel syndrome. An alpha L iduronidase assay was performed confirming the diagnosis. The radiological assessment revealed macrocephaly, thickening of the cranial vault, an elongated J-shaped sella turcica, a short thorax, short and thick clavicles, widened, oarshaped ribs tapering at their vertebral insertion, ''spur'' vertebrae, thoracolumbar kyphoscoliosis, narrowed pelvis with coxa-valga and genu valgum, small and deformed carpal and tarsal bones with cortical thinning of long bones.

Discussion
The term dysostosis multiplex is used to describe skeletal abnormalities seen in MPS I that are often early and prominent. The progressive accumulation of GAGs led to an increase in chondrocyte apoptosis favoring the production of pro-inflammatory cytokines (TNFa, IL-1), chemokines and metalloproteases. This results in a degradation of the cartilaginous matrix, increased by the mechanical stresses, the disturbance of endochondral ossification, particularly in the sites subjected to articular mechanical stresses. That could explain the focal defect of the ossification of certain cartilaginous sites leading to this multiple dysplasia. At the axial level, the vertebrae can be oval shaped and flattened (platyspondyly). In the lower limbs, coxo-femoral abnormalities (coxa valga, splayed or flattened acetabulum), epiphyseal alterations, genu valgum, and hypoplasia of the iliac bones can be found. The metacarpal bones take on a tapered appearance like sucked candy cane and the interphalangeal joints of the hands and feet are dysplastic. Hypoplasia of the odontoid process leads to potentially serious cervical instability. Regular monitoring by MRI is necessary to avoid the risk of spinal cord section. The early introduction of enzyme replacement therapy led to a slower progression of symptoms, with improved growth, joint mobility and physical capacity, and stability over time, especially when associated with an appropriate rehabilitation care.

Conclusion
Even if Hurler syndrome is rare, it is still underdiagnosed, it can give various and varied clinico-radiographic features and potentially severe disabilities. Early diagnosis is essential since enzyme replacement therapy could stop or slow down the evolution to irreversible tissue damage.

Introduction
Behç et's disease is a chronic, relapsing, multisystem vasculitis. The diagnosis is essentially clinical, due to the absence of specific biological criteria, which remains very difficult to establish in pediatric age because of often insidious or atypical disease onset. The association of Pseudo Inflammatory Non-Specific Tumors (PTINS) E POSTERS ii33